Gut Microbiota, Inflammatory Bowel Disease, and Cancer: The Role of Guardians of Innate Immunity

Inflammatory bowel diseases (IBDs) are characterized by a persistent low-grade inflammation that leads to an increased risk of colorectal cancer (CRC) development. Several factors are implicated in this pathogenetic pathway, such as innate and adaptive immunity, gut microbiota, environment, and xenobiotics. At the gut mucosa level, a complex interplay between the immune system and gut microbiota occurs; a disequilibrium between these two factors leads to an alteration in the gut permeability, called ‘leaky gut’. Subsequently, an activation of several inflammatory pathways and an alteration of gut microbiota composition with a proliferation of pro-inflammatory bacteria, known as ‘pathobionts’, take place, leading to a further increase in inflammation. This narrative review provides an overview on the principal Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs), focusing on their recognition mechanisms, signaling pathways, and contributions to immune responses. We also report the genetic polymorphisms of TLRs and dysregulation of NLR signaling pathways that can influence immune regulation and contribute to the development and progression of inflammatory disease and cancer

The Notch1 signaling pathway directly modulates the human RANKL-induced osteoclastogenesis

Abstract Notch signaling is an evolutionary conserved pathway with a key role in tissue homeostasis, differentiation and proliferation. It was reported that Notch1 receptor negatively regulates mouse osteoclast development and formation by inhibiting the expression of macrophage colony-stimulating factor in mesenchymal cells. Nonetheless, the involvement of Notch1 pathway in the generation of human osteoclasts is still controversial. Here, we report that the constitutive activation of Notch1 signaling induced a differentiation block in human mononuclear CD14+ cells directly isolated from peripheral blood mononuclear cells (PBMCs) upon in vitro stimulation to osteoclasts. Additionally, using a combined approach of single-cell RNA sequencing (scRNA-Seq) simultaneously with a panel of 31 oligo-conjugated antibodies against cell surface markers (AbSeq assay) as well as unsupervised learning methods, we detected four different cell stages of human RANKL-induced osteoclastogenesis after 5 days in which Notch1 signaling enforces the cell expansion of specific subsets. These cell populations were characterized by distinct gene expression and immunophenotypic profiles and active Notch1, JAK/STAT and WNT signaling pathways. Furthermore, cell–cell communication analyses revealed extrinsic modulators of osteoclast progenitors including the IL7/IL7R and WNT5a/RYK axes. Interestingly, we also report that Interleukin-7 receptor (IL7R) was a downstream effector of Notch1 pathway and that Notch1 and IL7R interplay promoted cell expansion of human RANKL-induced osteoclast progenitors. Taken together, these findings underline a novel cell pattern of human osteoclastogenesis, outlining the key role of Notch1 and IL-7R signaling pathways

The circadian clock circuitry modulates leukemia initiating cell activity in T-cell acute lymphoblastic leukemia

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, characterized by restricted cellular subsets with asymmetrically enriched leukemia initiating cell (LIC) activity. Nonetheless, it is still unclear which signaling programs promote LIC maintenance and progression. Methods Here, we evaluated the role of the biological clock in the regulation of the molecular mechanisms and signaling pathways impacting the cellular dynamics in T-ALL through an integrated experimental approach including gene expression profiling of shRNA-modified T-ALL cell lines and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) of leukemic cells. Patient-derived xenograft (PDXs) cell subsets were also genetically manipulated in order to assess the LIC activity modulated by the loss of biological clock in human T-ALL. Results We report that the disruption of the circadian clock circuitry obtained through shRNA-mediated knockdown of CLOCK and BMAL1 genes negatively impacted the growth in vitro as well as the activity in vivo of LIC derived from PDXs after transplantation into immunodeficient recipient mice. Additionally, gene expression data integrated with ChIP-Seq profiles of leukemic cells revealed that the circadian clock directly promotes the expression of genes, such as IL20RB, crucially involved in JAK/STAT signaling, making the T-ALL cells more responsive to Interleukin 20 (IL20). Conclusion Taken together, our data support the concept that the biological clock drives the expression of IL20R prompting JAK/STAT signaling and promoting LIC activity in T-ALL and suggest that the selective targeting of circadian components could be therapeutically relevant for the treatment of T-ALL patients

Ecosystem vulnerability to alien and invasive species: a case study on marine habitats along the Italian coast

1. Spread of alien species (AS) is a serious threat to marine habitats and analysis of principal descriptors of their occurrence is pivotal to set reliable conservation strategies. 2. In order to assess the susceptibility of marine habitats to biological invasions, a dataset was gathered of the occurrence of 3899 species from 29 phyla, taken from 93 marine sites located along the Italian coast in the period 2000\u20132012. 3. In total, 61 AS belonging to 11 phyla have been recorded. Invertebrates were the most represented (63%). Alien species were found in all the habitats examined (EUNIS, level 2), although they showed highest abundance in benthic habitats. Most of the AS were associated with a single EUNIS habitat, while some of them were present in more than one habitat. Trans-habitat occurrence suggests the potential invasiveness of AS. 4. According to statistical analysis, AS recorded could have been more numerous, since some of the marine habitats seemed to be still unsaturated. The model that best describes the spread of AS takes account of both native species richness (Rn) and EUNIS habitat type as explanatory variables. The number of observed AS was directly related to Rn and it was highest in rocky circalittoral and infralittoral habitats. 5. The results of this macro-ecological study focus on the importance of performing large-scale studies, since adopting ecosystem approaches to marine invasion management seems especially fruitful. 6. The results, moreover, highlight the importance of AS monitoring of different habitats, from those subjected to anthropogenic pressure, historically considered to be hubs of introduction of AS, to the most biologically rich and diverse marine habitats. Indeed, it is necessary to set monitoring strategies to detect the introduction, the distribution and persistence of AS over time. These recommendations are especially significant in the light of the strategic plans currently under formulation in Mediterranean countries with regard to AS monitorin